Multicomponent crystalline system of rosuvastatin calcium salt and vanillin

ABSTRACT

A novel solid form of Rosuvastatin comprises as the active ingredient a salt of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid] and vanillin or vanillin derivatives. The crystal comprising the two components, and minor amounts of water, shows improved properties such as crystallization behavior stability and decreased hydroscopic behavior.

The present invention relates to a multicomponent system comprisingrosuvastatin calcium salt and vanillin or vanillic acid topharmaceutical preparations comprising said system, and specifically toa homogenous crystalline phase (cocrystal) comprising rosuvastatincalcium and vanillin. The invention also relates to processes forpreparing said multicomponent system and crystalline phase. Theinvention also relates to compositions comprising said multicomponentsystem or crystalline phase and a pharmaceutically acceptable carrier,and to methods of using said multicomponent system or crystalline phaseto treat a disease condition wherein inhibition of HMG CoA reductase isbeneficial.

Rosuvastatin calcium is known as the calcium salt ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid], specifically the calcium salt of formula (1)

It is known to inhibit the HMG-CoA reductase, and subsequently suppressthe biosynthesis of cholesterol. The compound is also known asRosuvastatin hemicalcium salt, corresponding to half of the molecularweight shown in the above formula (1). Rosuvastatin calcium is useful inthe treatment of hypercholesterolemia, hyperlipoproteinemia, andatherosclerosis. Rosuvastatin calcium may form hydrates with a varyingcontent of water.

In WO 00/42024 is disclosed a crystalline form, hereafter referred to asform A ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and hydrates thereof, which are prepared bydissolving the amorphous form in a mixture of water and an organicsolvent such as acetone or acetonitrile under heating and then coolingthe solution to precipitate crystalline form A.

WO 06/079611 discloses some further crystalline forms of rosuvastatincalcium including form B. Further documents disclosing certaincrystalline forms of rosuvastatin calcium are EP-A-1663989 andUS-A-2008-176878.

Existing solid forms of rosuvastatin calcium still leave room forimprovement of physical as well as biological characteristics. Thereexists a need for other solid forms, especially crystalline forms, ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt for sufficient diversity on crystalline materials tooptimize manufacture, formulation and biological efficiency.

SUMMARY OF THE INVENTION

The invention provides a novel solid form of rosuvastatin calciumcharacterized by a content of vanillin or vanillin derivatives and,consequently, novel pharmaceutical formulations containing this form.The invention further provides a novel crystalline form of rosuvastatincalcium, and processes for manufacture thereof.

Crystalline forms often show desired different physical and/orbiological characteristics which may assist in the manufacture orformulation of the active compound, to the purity levels and uniformityrequired for regulatory approval. The present solid form, especiallycrystalline form, may possess improved pharmacological characteristics,for example, improved bioavailability, thus offering enhancedpossibilities to modulate and design improved drug products.

DETAILED DESCRIPTION OF THE INVENTION

The solid form of the invention is a composite comprising twocomponents, which are a rosuvastatin salt, especially rosuvastatincalcium, and vanillin or vanillin derivatives like vanillic acid,acetovanillon, isovanillin, ethylvanillin, or ortho-vanillin within onesingle phase:

More specifically, the invention provides a multicomponent molecularcrystal (i.e. a co-crystal) containing a salt of Rosuvastatin andvanillin, preferably the hemi Ca salt ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] and vanillin or vanillic-acid, acetovanillon, isovanillin,ethylvanillin, or ortho-vanillin.

The solid phase generally contains 0.1 to 1.5 molar parts of vanillin orvanillic-acid, acetovanillon, isovanillin, ethylvanillin, orortho-vanillin, on 1 molar unit of[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid].

More specifically, the solid phase contains 0.4 to 0.6 molar parts, ofvanillin on 1 molar unit[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid]. The salt is preferably the calcium or sodium salt, especially thehemi calcium salt. Preferred are is a ratio of about 0.5:1 (i.e. 1:2adduct).

The Invention Thus Includes

i) a multicomponent molecule crystal containing a salt ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] and of vanillin or vanillic-acid or acetovanillon or isovanillinor ethylvanillin, or ortho-vanillin

ii) a multicomponent molecular crystal containing a hemi Ca salt ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] and vanillin or vanillic-acid or acetovanillon or isovanillin orethylvanillin, or ortho-vanillin;

iii) a multicomponent molecular crystal containing containing 0.1 to 1.5molar parts, preferably 0.3 to 1.1 molar parts, and much preferred 0.4to 0.6 molar parts, Vanillin or vanillic-acid or acetovanillon orisovanillin or ethylvanillin, or ortho-vanillin; on 1 molar part ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] as calcium and preferably as hemi calcium salt;

iv) a solid form as defined under i-iii consisting essentially ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt, vanillin or vanillic-acid or acetovanillon orIsovanillin or ethylvanillin or ortho-vanillin as minor component byweight.

v) Preferred is a solid form as defined under i-iv consistingessentially ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and vanillin as a component.

Preferred solid form may be further characterized by its highcrystallinity and/or high melting point of above 100° C. (m.p. e.g. fromthe range 100-120° C., especially from the range 102-110° C.) and highmelting enthalpy Δ H>40 J/g (see present examples). While showing a goodsolubility, the present solid form provides better stability, andprovides advantages in processing due to its good crystallizationproperties (crystallisation from water without co solvents).

Vanillin and rosuvastatin are present in the same solid phase,preferably in the same crystalline phase, i.e. forming a co-crystal;hereinafter designated as form E. The invention thus further pertains toa novel crystalline form of rosuvastatin calcium, which crystalline formis characterized by containing vanillin within its crystallinestructure, e.g. in amounts as indicated above. A preferred novelcrystalline form generally exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)25.4 (vw).18.0 (S) 9.5 (s) 7.7 (s), 4.73 (s), 4.62 (vs), 4.52 (s), 4.36(vs), 4.26 (vs), 4.01 (s), 3.84 (s), 3.66 (s), 3.6 0 (vs).

More specifically, the present invention comprises a crystalline form ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and hydrates thereof, which exhibits a characteristicX-ray powder diffraction pattern with characteristic peaks expressed ind-values (Å) as shown in the below table:

d-spacing [Å] Rel. Int. qualitatively 25.4 vw 18.0 vs 15.4 vw 12.8 m10.7 w 9.5 s 9.0 w 8.5 m 7.7 s 6.2 w 5.73 m 5.65 m 5.43 m 5.20 w 4.97 w4.73 s 4.62 vs 4.52 s 4.36 vs 4.26 vs 4.01 s 3.84 s 3.66 s 3.60 vs 3.43vw 3.35 vw 3.27 w 3.20 w 3.11 w 3.05 vw 2.93 w 2.82 w Here and in thefollowing the abbreviations in brackets mean: (vs) = very strongintensity; (s) = strong intensity; (m) = medium intensity; (w) = weakintensity. (vw) = very-weak, intensity

In still another preferred embodiment, the present invention comprises acrystalline form D ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and hydrates thereof, which exhibits characteristicX-ray powder diffraction patterns as exhibited in FIG. 1.

Another object of the invention is a process for the preparation ofcrystalline form E ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](R3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt (Rosuvastatin calcium) and hydrates thereof whichcomprises the steps of

a) providing vanillin, or a suitable derivative thereof (vanillic acidor isovanillin or orthovanillin or ethylvanillin or acetovanillon),

b) providing a solution of Rosuvastatin calcium (e.g. crude Rosuvastatincalcium or another form of Rosuvastatin in combination with anequivalent or excess amount of calcium, e.g. from synthesis) in asuitable solvent,

c) combining the solutions or suspension provided in steps (a) and (b),and

d) separating the precipitate and drying.

Step (a) usually comprises providing vanillin in solid form, or as asolution of vanillin in water, or water containing minor amounts of awater miscible solvent as defined for (b) below.

The solvent used in step (b) is water or a water miscible organicsolvent such as an alcohol (e.g. methanol, ethanol, propanol, butanol),or an ester (such as ethyl acetate, methyl acetate), ethers such asmethyl-tert.butylether, or an aliphatic ketone (e.g. acetone, methylethyl ketone), or mixture of such solvents, or such a solvent withwater. Solutions or suspension according to steps (a) and (b) preferablyare concentrated solutions.

The concentration of rosuvastatin calcium may range from 0.1 to about300 mg/ml of solvents (including water), preferably from 5 to 200 mg/ml.

The process is preferably carried out in the temperature range 15-50°C., for example at ambient temperature. In a preferred process, step (c)is carried out at a temperature from the range 20-60° C. or the mixtureis heated to a temperature from said range, e.g. about 50° C. Thesuspension thus tempered is then preferably cooled before step (d). In apreferred process, the step is accompanied by seeding with crystals ofform E (e.g. 1-10% b.w. of the total amount of rosuvastatin) at atemperature of about 20-50° C.

Ambient temperature means in the context of the invention a temperaturerange at room temperature, comprising 20 to 30° C. and preferably about20to 25° C.

As an alternative, the present solid form may be prepared bymelt-extruding a suitable mixture of the Rosuvastatin salt and thevanillin component (vanillin or vanillic acid or isovanillin orortho-vanillin or ethylvanillin or acetovanillon).

Crystal form E is isolated by filtering off the crystals and drying,e.g. in vacuum, an inert gas flow or both at ambient temperature, orelevated temperatures up to 60° C.

Form E is thermodynamically stable and can be dried at elevatedtemperatures, e.g. below 80° C., and is obtained as a fine powder withtypical particle size distributions with the median size between 1 and50 μm, preferably between 1 to 10 μm. This particle size range ensures afast dissolution profile, while retaining the favorable handlingproperties in the formulation process.

Form E is less prone to water uptake under humidity, and is easy toformulate compared to Crystal form A.

Crystal form A¹⁾ Crystal form E²⁾ Water vapor sorption:  6.2% 2.6% watercontent after 2 h at 50% r.h. Water vapor sorption: 10.1% 5.0% watercontent after 5 h at 95% r.h.

Present Form E generally contains minor amounts of water, mainly withinits crystal structure, the amounts usually ranging from 1.5 to 5% ofwater, relative to the total weight of the solid phase, especially ofthe crystalline form E.

The solid form E may be used in pharmaceutical compositions in the sameway as other forms of Rosuvastatin calcium previously known.Additionally, present form E based on any pharmaceutically acceptablesalt of rosuvastatin, such as sodium or calcium salt, may be employed asan intermediate or starting material to produce the pure activeingredient, e.g. in form of crystal form A.

The present invention is also directed to a pharmaceutical compositioncomprising a solid form containing vanillin, or especially crystal formE, ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and hydrates thereof, and a pharmaceuticallyacceptable carrier or diluent.

The amount of solid (especially crystalline) forms ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and hydrates thereof substantially depends on type offormulation and desired dosages during administration time periods. Theamount in an oral formulation may be from 0.1 to 200 mg, preferably from0.5 to 100 mg, and more preferably from 1 to 50 mg.

Oral formulations may be solid formulations such as capsules, tablets,pills and troches, or liquid formulations such as aqueous suspensions,elixirs and syrups. Solid and liquid formulations encompass alsoincorporation of the present solid form, especially crystal form E, intoliquid or solid food.

The solid forms according to the invention may be directly used aspowders (micronized particles), granules, suspensions or solutions, orthey may be combined together with other pharmaceutically acceptableingredients in admixing the components and optionally finely dividethem, and then filling capsules, composed for example from hard or softgelatine, compressing tablets, pills or troches, or suspend or dissolvethem in carriers for suspensions, elixirs and syrups. Coatings may beapplied after compression to form pills.

Pharmaceutically acceptable ingredients are well known for the varioustypes of formulation and may be for example binders such as natural orsynthetic polymers, excipients, lubricants, surfactants, sweetening andother flavouring agents, coating materials, preservatives, dyes,thickeners, adjuvants, antimicrobial agents and carriers for the variousformulation types.

Examples for binders are gum tragacanth, acacia, starch, gelatine, andbiological degradable polymers such as homo- or co-polyesters ofdicarboxylic acids, alkylene glycols, polyalkylene glycols and/oraliphatic hydroxyl carboxylic acids; homo- or co-polyamides ofdicarboxylic acids, alkylene diamines, and/or aliphatic amino carboxylicacids; corresponding polyester-polyamide-co-polymers, polyanhydrides,polyorthoesters, polyphosphazene and polycarbonates. The biologicaldegradable polymers may be linear, branched or crosslinked. Specificexamples are poly-glycolic acid, poly-lactic acid, andpoly-d,l-lactide/glycolide. Other examples for polymers arewater-soluble polymers such as polyoxaalkylenes (polyoxaethylene,polyoxapropylene and mixed polymers thereof, poly-acrylamides andhydroxylalkylated polyacrylamides, poly-maleic acid and esters or-amides thereof, poly-acrylic acid and esters or -amides thereof,poly-vinylalcohol und esters or -ethers thereof, poly-vinylimidazole,poly-vinylpyrrolidon, und natural polymers like chitosan, carragenan orhyaluronic aid.

Examples for excipients are phosphates such as dicalcium phosphate.

Examples for lubricants are natural or synthetic oils, fats, waxes, orfatty acid salts like magnesium stearate.

Surfactants may be anionic, anionic, amphoteric or neutral. Examples forsurfactants are lecithin, phospholipids, octyl sulfate, decyl sulfate,dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and octadecylsulfate, Na oleate or Na caprate, 1-acylaminoethane-2-sulfonic acids,such as 1-octanoylaminoethane-2-sulfonic acid,1-decanoylaminoethane-2-sulfonic acid,1-dodecanoylaminoethane-2-sulfonic acid,1-tetradecanoylaminoethane-2-sulfonic acid,1-hexadecanoylaminoethane-2-sulfonic acid, and1-octadecanoylaminoethane-2-sulfonic acid, and taurocholic acid andtaurodeoxycholic acid, bile acids and their salts, such as cholic acid,deoxycholic acid and sodium glycocholates, sodium caprate or sodiumlaurate, sodium oleate, sodium lauryl sulphate, sodium cetyl sulphate,sulfated castor oil and sodium dioctylsulfosuccinate,cocamidopropylbetaine and laurylbetaine, fatty alcohols, cholesterols,glycerol mono- or -distearate, glycerol mono- or -dioleate and glycerolmono- or -dipalmitate, and polyoxyethylene stearate.

Examples for sweetening agents are sucrose, fructose, lactose oraspartam.

Examples for flavouring agents are peppermint, oil of wintergreen orfruit flavours like cherry or orange flavour.

Examples for coating materials gelatine, wax, shellac, sugar orbiological degradable polymers.

Examples for preservatives are methyl or propylparabens, sorbic acid,chlorobutanol, phenol and thimerosal.

Examples for adjuvants are fragrances.

Examples for thickeners are synthetic polymers, fatty acids and fattyacid salts and esters and fatty alcohols.

Examples for liquid carriers are water, alcohols such as ethanol,glycerol, propylene glycol, liquid polyethylene glycols, triacetin andoils. Examples for solid carriers are talc, clay, microcrystallinecellulose, silica, alumina and the like.

The formulation according to the invention may also contain isotonicagents, such as sugars, buffers or sodium chloride.

The solid forms according to the invention may also be formulated aseffervescent tablet or powder, which disintegrate in an aqueousenvironment to provide a drinking solution.

A syrup or elixir may contain the cocrystal of the invention, sucrose orfructose as sweetening agent a preservative like methylparaben, a dyeand a flavouring agent.

The dosages include dosages suitable for oral, buccal, rectal,parenteral (including subcutaneous, intramuscular, and intravenous),inhalant and ophthalmic administration. Although the most suitable routein any given case will depend on the nature and severity of thecondition being treated, the most preferred route of the presentinvention is oral. The dosages may be conveniently presented in unitdosage form and prepared by any of the methods well-known in the art ofpharmacy.

Dosage forms include solid dosage forms, like tablets, powders,capsules, suppositories, sachets, troches and losenges as well as liquidsuspensions and elixirs. While the description is not intended to belimiting, the invention is also not intended to pertain to truesolutions of Rosuvastatin calcium whereupon the properties thatdistinguish the solid forms of Rosuvastatin calcium are lost. However,the use of the novel forms to prepare such solutions is considered to bewithin the contemplation of the invention.

Capsule dosages, of course, will contain the solid composition within acapsule which may be made of gelatin or other conventional encapsulatingmaterial. Tablets and powders may be coated. Tablets and powders may becoated with an enteric coating.

The enteric coated powder forms may have coatings comprising phthalicacid cellulose acetate, hydroxypropylmethyl-cellulose phthalate,polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer ofstyrene and maleic acid, a copolymer of methacrylic acid and methylmethacrylate, and like materials, and if desired, they may be employedwith suitable plasticizers and/or extending agents. A coated tablet mayhave a coating on the surface of the tablet or may be a tabletcomprising a powder or granules with an enteric-coating.

Slow release formulations may also be prepared from the crystal formaccording to the invention in order to achieve a controlled release ofthe active agent in contact with the body fluids in the gastrointestinal tract, and to provide a substantial constant and effectivelevel of the active agent in the blood plasma. The crystal forms may beembedded for this purpose in a polymer matrix of a biological degradablepolymer, a water-soluble polymer or a mixture of both, and optionallysuitable surfactants. Embedding can mean in this context theincorporation of micro-particles in a matrix of polymers. Controlledrelease formulations are also obtained through encapsulation ofdispersed microparticles or emulsified micro-droplets via knowndispersion or emulsion coating technologies.

The crystal forms of the invention are also useful for administering acombination of therapeutic effective agents to an animal. Such acombination therapy can be carried out in using at least one furthertherapeutic agent which can be additionally dispersed or dissolved in aformulation.

The crystal forms of this invention and its formulations respectivelycan be also administered in combination with other therapeutic agentsthat are effective to treat a given condition to provide a combinationtherapy.

The crystal forms and the pharmaceutical composition according to theinvention are highly suitable for effective treatment of disorders inconnection with need of inhibiting the HMG-CoA reductase, andsubsequently suppressing the biosynthesis of cholesterol. Crystallineforms of this invention and pharmaceutical composition are useful in thetreatment of hypercholesterolemia, hyperlipoproteinemia, andatherosclerosis.

An object of the invention is also a therapeutic method for producing anHMG-CoA reductase inhibiting effect in a mammal comprising administeringto a mammal in need of such therapy, an effective amount of the presentcomposite containing vanillin, especially crystal form E, ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt, and hydrates thereof.

The multicomponent crystal of the invention may be used as singlecomponent or as mixtures with other solid forms, which may becrystalline or amorphous.

As to the novel multicomponent crystal of Rosuvastatin calcium it ispreferred that these contain 25-100% by weight, especially 50-100% byweight, based on the total amount of Rosuvastatin calcium. Preferably,such an amount of the novel multicomponent crystal forms of Rosuvastatincalcium is 75-100% by weight, especially 90-100% by weight. Highlypreferred is an amount of 95-100% by weight.

Another object of the invention is a method of delivering a solid formofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and/or hydrates thereof to a host, which methodcomprises administering to a host an effective amount of said solidform, especially crystal form E, according to the invention.

A further object of the invention is the use of a crystal form D and/orsolid form containing vanillin, ofbis[(E)-744-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt, and hydrates thereof, for the manufacture of amedicament useful in the treatment of disorders in connection with needof inhibiting the H MG-CoA reductase, and subsequently suppressing thebiosynthesis of cholesterol, and especially useful in the treatment ofhypercholesterolemia, hyperlipoproteinemia, and atherosclerosisin in amammal, such as a human; and the solid forms according to the inventionfor use in medical therapy.

The following examples illustrate the invention.

Wherever noted, room temperature depicts a temperature from the range20-25° C.; percentages are given by weight, if not indicated otherwise.

Abbreviations:

DMSO dimethyl sulfoxide

HPLC high pressure liquid chromatography

NMR nuclear magnetic resonance

FTIR Fourier-transformation infrared spectrometry

r.h. relative humidity (air, if not indicated otherwise)

TG thermogravimetry

DSC differential scanning calorimetry

v/v volume by volume

PXRD Powder X-ray diffraction

Instrumental

PXRD is carried out with a Bruker D8 Advance powder X-ray diffractometerusing Cu_(K-alpha) radiation in reflection (Bragg-Brenatno) geometry. 2θvalues are accurate within an error of ±0.1-0.2°. The samples areprepared without any special treatment other than the application ofslight pressure to get a flat surface. About 3-5 mg of the sample areplaced on a 0.1 mm depth standard silicon single crystal sample holder.The tube voltage is 40 kV and current was 40 mA. The PXRD diffractometeris equipped with a LynxEye detector. A variable divergence slight isused with a 3° window. The step size is 0.02° 2θ with a step time of 37seconds. The samples are rotated at 0.5 rps during the measurement.

Thermogravimetry coupled to infrared spectroscopy (TG-FTIR):

The thermo gravimetric measurements are carried out with a NetzschThermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer IFS 28or Vector 22 (sample pan with a pinhole, N2 atmosphere, heating rate 10K/min, range 25° C. to 250° C.).

DSC:

Differential scanning calorimetry is carried out with a Perkin ElmerDSC7 using hermetically closed gold sample pans. Heating rate: 10K/minute.

1 H-NMR:

The 1 H-NMR spectra are recorded on a Bruker DPX 300 spectrometer.Solvent: DMSO-d6.

Experimental

Solvents: For all experiments, Fluka or Sigma Aldrich grade solvents areused. Selected solvents are dried using 3 or 4 A molecular sieves.

Crystallization Experiments:

The crystallization experiments are performed in Supelco glass vialsusing magnetic stirrers.

Aqueous Solubility Determination:

Approximately 0.5 mL of doubly distilled water is added to 10 to 40 mgof the substance to be measured. The resulting suspension isequilibrated in a temperature-controlled Eppendorf Thermomixer Comfortshaker for 2 h and 24 h at 25° C. at a shaking rate of 400 rpm. After 24h the solid phase is recovered by filter centrifugation (0.10-μm PVDFmembrane) and examined by XRPD. Concentrations in the filtrate after 2 hand 24 h (i.e., saturated solutions) are determined using HPLC. The pHof the saturated solution is determined with a Metrohm 713 pH meter.

EXAMPLE 1 Preparation of Cocrystal with Vanillin (Form E) (SeedingMaterial)

125 mg of amorphous or mesomorphic Rosuvastatin hemicalcium salt and 38mg of vanillin are suspended in 10 mL of water at room temperature. Thesystem is sonicated for 1 minute and stirred for 4 days at roomtemperature and sonicated once per day. The suspension formed isfiltered, air dried for 10 minutes and further dried at 50° C./30 mbarfor 2 hours. The yield is 76 mg (approx. 53%). XRPD shows the pattern ofcrystal form E, and TG-FTIR shows a mass loss of 1.7% (water; 25° C. to150° C.). 1H-NMR (measured in DMSO-d6) shows the spectrum of a mixtureof Rosuvastatin hemi-calcium salt and vanillin (molar ratio Rosuvastatinhemicalcium salt:vanillin 1:0.6).

DSC in a closed sample pan shows an endothermal effect with a peaktemperature of 103.2° C. (65 J/g).

EXAMPLE 2 Preparation of Co-Crystal with Vanillin (Form E)

502 mg of amorphous or mesomorphic Rosuvastatin hemicalcium salt aresuspended in 20 mL of a saturated solution of vanillin in water at roomtemperature. The suspension is seeded with approx. 10 mg of theRosuvastatin hemicalcium salt vanillin co-crystal (product of example1), heated to 50° C. and stirred for 1 hour at 50° C. The suspension iscooled to room temperature and stirred for 16 hours at room temperature.To the easily stirrable suspension, 10 mL of water are added and thesuspension is stirred for an additional 1.5 hours. The suspension isfiltered, washed two times with 5 mL of water, air dried for 10 minutesand further dried at 50° C./30 mbar for 2 hours. The yield is 481 mg(approximately 83%). XRPD shows the pattern of crystal form E, andTG-FTIR shows a mass loss of 1.6% (water; 25° C. to 150° C.). 1H-NMR(measured in DMSO-d6) shows the spectrum of a mixture of Rosuvastatinhemicalcium salt and vanillin (molar ratio Rosuvastatin hemicalciumsalt:vanillin 1:0.5). DSC in a closed sample pan shows an endothermaleffect with a peak temperature of 107.7° C. (62 J/g)

EXAMPLE 3 Characterization of Co-Crystal

In order to further investigate the product obtained in examples 1 and2, some additional experiments and characterizations are carried out:

(a) z.B. 1 H-NMR spectroscopy shows that crystal form E according toexample 1 contains Rosuvastatin and Vanillin at a molar ratio of 1:0.6,and that crystal form E according to example 2 contains Rosuvastatineand Vanillin at a molar ratio of 1:0.5

(b) The DSC diagram does not indicate the presence of any of the crystalforms of vanillin given in publication Svärd-2007 (Journal ofPharmaceutical Sciences 96, 2007, 2390-2398) or the amorphous form. Themelting peak does not indicate eutectic impurities. The melting peaktemperature of both samples is well above the melting temperatures ofthe known crystal forms of vanillin.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: Powder X-Ray Diffraction pattern of Rosuvastatin hemicalciumsalt/crystal form E (1:0.5 co-crystal with vanillin)

1. A single phase solid form of abis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] salt comprising vanillin or vanillic acid or isovanillin orortho-vanillin or ethylvanillin or acetovanillon.
 2. A single phasesolid form of abis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] salt comprising vanillin.
 3. Solid form of claim 2 wherein thesalt ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] is a calcium salt.
 4. Solid phase according to claim 1 containing0.1 to 1.5 molar parts of vanillin or vanillic acid, acetovanillon,isovanillin, ethylvanillin or ortho-vanillin on 1 molar unit[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoicacid].
 5. Solid form according to claims 1 containing 0.2 to 1 molarparts, of vanillin on 1 molar unit of[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoicacid].
 6. Solid form according to claim 1, which is a molecular crystal.7. Solid form according to claim 1, consisting essentially ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt, vanillin, and water as minor component by weight. 8.Solid form according to claim 1, which is a crystalline form ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt with vanillin, and/or hydrates thereof, exhibiting aX-ray powder diffraction pattern with characteristic peaks expressed ind-values (Å): in d-values (A) 25.4 (vw),18.0 (s) 9.5 (s) 7.7 (s), 4.73(s), 4.62 (vs), 4.52 (s), 4.36 (vs), 4.26 (vs), 4.01 (s), 3.84 (s), 3.66(s), 3.60 (vs).
 9. Solid form according to claim 1, which is acrystalline form ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt with vanillin, and/or hydrates thereof, which ischaracterized by a melting peak temperature greater than 90° C. and anenthalpy of fusion greater than 40 Joule per gram when 2.5 to 4.0 mg ofa sample is measured in a gold sample pan hermetically sealed at arelative humidity of 25+/−10%.
 10. Solid form according to claim 1,comprising a crystalline form ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt with vanillin, and/or hydrates thereof, whichexhibits a characteristic X-ray powder diffraction pattern essentiallyas exhibited in FIG.
 1. 11. Process for the preparation and/orpurification of Rosuvastatin calcium, according to claim 1, whichcomprises the steps of a) providing a solution or suspension of vanillinin water, b) adding Rosuvastatin calcium salt to the solution as solidor as suspension in water, and c) separating the precipitate and drying.12. Pharmaceutical composition comprising the solid form according toclaim 1, and a pharmaceutically acceptable carrier or diluent.
 13. Atherapeutic method for producing an HMG-CoA reductase inhibiting effectin a mammal, which method comprises administering to a mammal in need ofsuch therapy, an effective amount of a solid form according to claim 1.14. A method of delivering a solid form ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt and/or hydrates thereof, which method comprisesadministering to a host an effective amount of a solid form according toclaim
 1. 15. (canceled)